Composition containing perilla frutescens fermented extract for prevention, alleviation, or treatment of sleep disorder

ABSTRACT

A pharmaceutical composition, a dietary supplement, or food containing a Perilla frutescens fermented extract is disclosed. The composition is useful for prevention or treatment of a sleep disorder. A composition or a fiber or fragrance composition containing a Perilla frutescens fermented extract is also disclosed. A method for treating sleep disorder employing the pharmaceutical composition, dietary supplement, food, or the fiber or fragrance composition is disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. Application No. 16/767,839filed May 28, 2020 (allowed), which is a National Stage of InternationalApplication No. PCT/KR2018/014558 filed Nov. 23, 2018, claiming prioritybased on Korean Patent Application No. 10-2017-0163476 filed Nov. 30,2017 and Korean Patent Application No. 10-2018-0078853 filed Jul. 6,2018.

GOVERNMENT SUPPORT

This invention was made, at least in part, with government support underGrant Identification ICT (2018K000277 and 2020-JDH-2-CG-1) awarded bythe Commercialization Promotion Agency for R&D Outcomes (COMPA), theMinistry of Science of Republic of Korea.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition or healthfunctional food composition comprising a Perilla frutescens fermentedextract for prevention or treatment of a sleep disorder.

In addition, the present invention relates to a composition or a fiberor fragrance composition comprising a Perilla frutescens fermentedextract for sleep improvement.

In addition, the present invention relates to a method for treatment ofa sleep disorder, the method comprising a step of administering aPerilla frutescens fermented extract to a patient with a sleep disorder.

In addition, the present invention relates to a use of a Perillafrutescens fermented extract for use in the preparation of a compositionfor treatment of a sleep disorder or for prevention or treatment of asleep disorder.

BACKGROUND ART

Sleep refers to a state in which conscious activity is resting with eyesclosed. This is an important step in replenishing the energy used duringdaytime activities and relieving fatigue accumulated by physicalactivity, and is simultaneously the time when most of the growthhormones required for human growth are secreted. In addition, the brain,which supervises all the physiological functions for maintaining ourbody’s life, needs to rest in order to maintain an appropriate activitybalance, and such rest occurs during sleep hours in most cases.Recently, the American Thoracic Society has recommended that adultssleep 6 to 9 hours a day.

However, sleep problems occur due to the exhausting and busy daily livesof modem people, the aging of the population, and the like, so that thenumber of patients receiving treatment has been increasing in recentyears, and it is expected that the number will continue to increase inthe future. Sleep-related disorders are directly detrimental to health,but recent studies show that the lack of sleep increases the risk ofdiabetes, heart disease, and obesity. In a study from the journal‘Sleep’ published in 2004, women who slept on average less than fivehours a night had significantly higher mortality rates than women whoslept seven hours a night.

Currently, administration of sleeping drugs, tranquilizers, stressrelievers, and the like is used as a general therapy to treat most ofthe sleep disorders. However, when these medicines are taken for a longperiod of 4 weeks or more, problems of dependence and drug side effectsoccur, and in the case of elderly people and pregnant women, theadministration of the drugs described above is restricted. Therefore,there is an increasing need for the development of a drug consisting ofa natural material which has few side effects and can effectively treatsleep disorders or improve sleep quality besides the aforementioneddrugs.

Perilla frutescens is an annual plant of the Lamiaceae family, is usedto treat various diseases such as coughs, sputum, pharyngolaryngitis,dyspepsia, boils, paralytic diabetes, and back pain, and is known tohave antibacterial or anticancer effects.

Japanese Patent Application No. 2004-219382 relates to a compositionhaving an action of promoting good sleep and a beverage containing thesame, and includes a Perilla frutescens leaf extract. The patentapplication discloses that ingestion of the aforementioned compositionhas an effect of inducing good sleep, such as prolonging of sleepingtime.

However, no studies and reports have been made on the effects of acomposition obtained by fermenting a Perilla frutescens extract with amicroorganism on the improvement of sleep quality such as sleep disordertreatment or sleep improvement.

DISCLOSURE Technical Problem

Thus, the present inventors confirmed that a Perilla frutescensfermented extract has effects of shortening sleep latency and increasingtotal sleeping time, confirmed these effects are superior compared toexisting drugs used for the treatment of a sleep disorder, and the like,thereby completing the present invention.

Therefore, an object of the present invention is to provide apharmaceutical composition or health functional food compositioncomprising a Perilla frutescens fermented extract for prevention ortreatment of a sleep disorder.

Another object of the present invention is to provide a composition or afiber or fragrance composition comprising a Perilla frutescens fermentedextract for sleep improvement.

Still another object of the present invention is to provide a method fortreatment of a sleep disorder, the method comprising a step ofadministering a Perilla frutescens fermented extract to a patient with asleep disorder.

Yet another object of the present invention is to provide a use of aPerilla frutescens fermented extract for use in the preparation of acomposition for treatment of a sleep disorder or for prevention ortreatment of a sleep disorder.

Technical Solution

To achieve the objects, the present invention may provide apharmaceutical composition comprising a Perilla frutescens fermentedextract for prevention or treatment of a sleep disorder.

The present invention may also provide a method for treatment of a sleepdisorder, the method comprising a step of administering a Perillafrutescens fermented extract to a patient with a sleep disorder.

The present invention may also provide a use of a Perilla frutescensfermented extract for use in the preparation of a composition fortreatment of a sleep disorder.

The present invention may also provide a Perilla frutescens fermentedextract for use in the prevention or treatment of a sleep disorder.

According to a preferred exemplary embodiment of the present invention,the fermented extract may be extracted from any one or more sitesselected from the group consisting of leaves, stems, flowers, fruit, andseeds of Perilla frutescens.

According to a preferred exemplary embodiment of the present invention,the fermented extract may be extracted with water, a C₁ to C₄ organicsolvent, or a mixture thereof as a solvent, and then fermented with afermentation strain.

According to a preferred exemplary embodiment of the present invention,the fermentation strain may be any one or more strains consisting ofbacillus, lactobacillus, and yeast.

According to a preferred exemplary embodiment of the present invention,the bacillus, the lactobacillus, and the yeast may be species belongingto the bacillus genus, the lactobacillus genus, and the Saccharomycesgenus, respectively.

According to a preferred exemplary embodiment of the present invention,the fermentation may be performed at 5° C. to 80° C. for 30 minutes to10 days.

According to a preferred exemplary embodiment of the present invention,the sleep disorder may be any one or more selected from the groupconsisting of disturbance of sleep induction, deep sleep disorder,halfway awakening, early awakening, insomnia, nightmares, somnambulism,narcolepsy, abnormal behavior during sleep, hypersomnia, sleep seizures,breathing-related sleep disorder, apnea syndrome, circadian rhythm sleepdisorders, parasomnia, restless leg syndrome, and periodic limb movementdisorder.

The present invention may also provide a health functional foodcomposition comprising a Perilia frutescens fermented extract forprevention or alleviation of a sleep disorder.

The present invention may also provide a composition comprising aPerilla frutescens fermented extract for sleep improvement.

According to a preferred exemplary embodiment of the present invention,the composition may be any one or more compositions selected from thegroup consisting of a food composition, a cosmetic composition, a dyecomposition, a pharmaceutical composition, and a quasi-drug composition.

The present invention may also provide a sleep aid comprising a Perillafrutescens fermented extract.

The present invention may also provide a fiber comprising a Perillafrutescens fermented extract for sleep improvement.

According to a preferred exemplary embodiment of the present invention,the fiber may be dyed with a Perilla frutescens fermented extract.

According to a preferred exemplary embodiment of the present invention,the fiber may be included in any one or more products selected from thegroup consisting of bedding, clothes, curtains, carpets, indoor shoes,towels, wallpaper, interior fabric coverings, dolls, and eye patches.

The present invention may also provide a fragrance compositioncomprising a Perilla frutescens fermented extract.

According to a preferred exemplary embodiment of the present invention,the composition may be comprised in any one or more products selectedfrom the group consisting of perfumes, aromas, oils, fragrances,detergents, and preparations for external application to the skin.

Hereinafter, the present invention will be described in more detail.

As described above, in the related art, when a drug such as a sleepingdrug or a sedative prescribed for treatment of a sleep disorder or thelike is continuously administered, there is a critical point at whichdependency or drug side effects occur(s). As a measure for overcomingthis, there is a need for developing a composition which has excellenteffects of treating a sleep disorder and the like while usingplant-derived natural materials.

A Perilla frutescens fermented extract according to the presentinvention is fermented using various microorganisms such as bacillus,and has effects of significantly shortening sleep latency andsignificantly increasing total sleeping time, and thus is effective as acomposition for prevention, alleviation, or treatment of a sleepdisorder.

As used herein, “sleep disorder” is a disease relating to sleep, andrefers to a condition in which sleep is disturbed by various factors. Asleep disorder may be classified according to its causes, but when it iscaused by emotional factors, it is called “nonorganic sleep disorder”,and when it is caused by physical factors, it is called “organic sleepdisorder”.

As used herein, “sleep improvement” refers to all the effects ofqualitatively or quantitatively alleviating various symptoms related tothe aforementioned sleep disorder and other symptoms that make itdifficult to sleep smoothly.

As used herein “sleep latency” refers to the time it takes to enter deepsleep. A sleep disorder in which one falls asleep but has difficultyentering deep sleep is called “disturbance of sleep induction”.

As used herein, “total sleeping time” refers to the time during whichsleep is maintained.

As used herein, “ Perilla frutescens fermented extract” means that aPerilla frutescens extract is first prepared, and then the extract isfermented using a fermentation strain.

Therefore, the present invention provides a pharmaceutical compositioncomprising a Perilla frutescens fermented extract for prevention ortreatment of a sleep disorder.

Perilla frutescens is also called Perilla frutescens Britton var.acutaKud, and is known to have antibacterial or anticancer effects. Perillafrutescens may also be used to cook rice used in California rolls orwith sushi, and may also be used as a dye to color food or dye fabrics,and the like.

In order to prepare a Perilla frutescens fermented extract, a Perillafrutescens extract is first prepared. The Perilla frutescens extract maybe extracted from above-ground parts such as the leaves, stems, flowersor fruit, or seeds of Perilla frutescens, but is preferably extractedfrom the above-ground parts such as the leaves, stems, flowers or fruitof Perilla frutescens, and is most preferably extracted from the leavesof Perilla frutescens. The extraction solvent may be water, a C₁ to C₄organic solvent, or a mixture thereof, but is preferably water or a C₁to C₄ alcohol, more preferably water, methanol, ethanol, or propanol,and most preferably water (Example 1).

As the fermentation strain which may be used to ferment the Perillafrutescens extract, bacillus, lactobacillus, or yeast may be used, andit is preferred to enhance the sleep improvement effect of the Perillafrutescens extract that the bacillus are species belonging to thebacillus genus, the lactobacillus are species belonging to thelactobacillus genus, and the yeast are species belonging to theSaccharomyces genus.

The bacillus may be any one or more bacillus genus bacteria selectedfrom the group consisting of bacillus subtilis, bacillus thuringiensis,bacillus licheniformis, bacillus amyloliquefaciens, bacillusstearothermophilus, bacillus coagulans, bacillus longum, bacilluspumilus, bacillus brevis, bacillus circulans, and bacillus polymyxa;

-   the lactobacillus may be any one or more lactobacillus genus    bacteria selected from the group consisting of lactobacillus    acidophilus, lactobacillus casei, lactobacillus gasseri,    lactobacillus bulgaricus, lactobacillus helveticus, lactobacillus    fermentum, lactobacillus paracasei, lactobacillus plantarum,    lactobacillus reuteri, lactobacillus rhamnosus, and lactobacillus    salivarius; and-   the yeast may be any one or more Saccharomyces genus bacteria    selected from the group consisting of Saccharomyces cerevisiae,    Saccharomyces uvarum, Saccharomyces ellipsoideus, Saccharomyces    carlsbergensis, Saccharomyces sake, Saccharomyces coreanus,    Saccharomyces lipolytica, Saccharomyces boulardii, and Saccharomyces    pastorianus.

The fermentation is carried out preferably at 5° C. to 80° C. for 30minutes to 10 days, more preferably at 20° C. to 40° C. for 3 days to 8days, and most preferably at 22° C. to 30° C. for 4 days to 6 days(Example 1).

The administration route of the Perilla frutescens fermented extract canbe oral or parenteral, and in the case of parenteral administration, thePerilla frutescens fermented extract may be administered via a routesuch as topical, injection, transdermal or nasal, but the route is notlimited thereto. The administration of the Perilla frutescens fermentedextract of the present invention may alleviate various symptoms relatedto sleep disorders and obtain other sleep improvement effects, so thatit is possible to satisfy the sleeping time recommended worldwide ordesired by individuals.

The sleep disorder of the present invention means all disorders whichexhibit abnormal symptoms related to sleep, but is preferably any one ormore selected from the group consisting of disturbance of sleepinduction, deep sleep disorder, halfway awakening, early awakening,insomnia, nightmares, somnambulism, narcolepsy, abnormal behavior duringsleep, hypersomnia, sleep seizures, breathing-related sleep disorder,apnea syndrome, circadian rhythm sleep disorders, parasomnia, restlessleg syndrome, and periodic limb movement disorder, but is not limitedthereto.

The pharmaceutical compositions of the present invention may be invarious oral or parenteral preparations. When the composition isformulated, the composition may be prepared using one or more buffers(for example, saline or PBS), antidiabetic agents, bacteriostats,chelating agents (for example, EDTA or glutathione), fillers, extenders,binders, adjuvants (for example, aluminum hydroxide), suspensions,thickeners, wetting agents, disintegrants or surfactants, diluents, orexcipients.

Examples of a solid preparation for oral administration include atablet, a pill, a powder, a granule, a capsule, and the like, and thesolid preparation is prepared by mixing one or more compounds with atleast one or more excipients, for example, starch (including cornstarch, wheat starch, rice starch, potato starch, and the like), calciumcarbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol,erythritol maltitol, cellulose, methyl cellulose, sodiumcarboxymethylcellulose and hydroxypropyl methylcellulose, gelatin, orthe like. For example, a tablet or a sugar tablet may be obtained byblending an active ingredient with a solid excipient, pulverizing theresulting blend, adding a suitable auxiliary agent thereto, and thenprocessing the resulting mixture into a granular mixture. Further, inaddition to a simple excipient, lubricants such as magnesium stearateand talc are also used.

A liquid preparation for oral administration corresponds to asuspension, a liquid for internal use, an emulsion, a syrup, and thelike, and the liquid preparation may include, in addition to water andliquid paraffin which are simple commonly used diluents, variousexcipients, for example, a wetting agent, a sweetener, a flavoringagent, a preservative, or the like. In addition, in some cases,cross-linked polyvinyl pyrrolidone, agar, alginic acid, sodium alginate,or the like may be added as a disintegrant, and an anti-coagulant, alubricant, a wetting agent, a flavoring agent, an emulsifier, anantiseptic, and the like may be additionally added.

Preparations for parenteral administration include an aqueous sterilesolution, a non-aqueous solvent, a suspension solvent, an emulsion, afreeze-dried preparation, a suppository, or the like. As the non-aqueoussolvent and the suspension solvent, it is possible to use propyleneglycol, polyethylene glycol, a vegetable oil such as olive oil, aninjectable ester such as ethyl oleate, and the like. As a base of thesuppository, it is possible to use Witepsol, Macrogol, Tween 61, cacaobutter, laurin fat, glycerol, gelatin, and the like.

The pharmaceutical composition of the present invention may beadministered orally or parenterally, and, when administeredparenterally, may be formulated in the form of a preparation forexternal application to the skin; an injection administeredintraperitoneally, intrarectally, intravenously, intramuscularly,subcutaneously, or intracerebroventricularly, or via cervicalintrathecal injection; a transdermal administration agent; or a nasalinhaler according to a method known in the art.

The injection must be sterilized and protected from contamination bymicroorganisms such as bacteria and fungi. Examples of a suitablecarrier for injection may be, but are not limited to, a solvent or adispersion medium including water, ethanol, polyols (for example,glycerol, propylene glycol, liquid polyethylene glycol, and the like),mixtures thereof, and/or vegetable oils. More preferably, as a suitablecarrier, it is possible to use an isotonic solution such as Hank’ssolution, Ringer’s solution, triethanolamine-containing phosphatebuffered saline (PBS) or sterile water for injection, 10% ethanol, 40%propylene glycol, and 5% dextrose, and the like. To protect theinjection from microbial contamination, various antimicrobial agents andantifungal agents such as paraben, chlorobutanol, phenol, sorbic acid,and thimerosal may be additionally included. Furthermore, in most cases,the injection may additionally include an isotonic agent such as sugaror sodium chloride.

Examples of the transdermal administration agent include a form such asan ointment, a cream, a lotion, a gel, a solution for external use, apaste, a liniment, and an aerosol. The transdermal administration asdescribed above means that an effective amount of an active ingredientcontained in a pharmaceutical composition is delivered into the skin vialocal administration thereof to the skin.

In the case of a preparation for inhalation, the extract used accordingto the present invention may be conveniently delivered in the form of anaerosol spray from a pressurized pack or a nebulizer using a suitablepropellant, for example, dichlorofluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. Inthe case of the pressurized aerosol, a dosage unit may be determined byproviding a valve for transferring a metered amount. For example, agelatin capsule and a cartridge for use in an inhaler or insufflator maybe formulated so as to contain a powder mixture of a compound and asuitable powder base such as lactose or starch. Formulations forparenteral administration are described in the document, which is aguidebook generally known in all pharmaceutical chemistry fields(Remington’s Pharmaceutical Science, 15th Edition, 1975. Mack PublishingCompany, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour).

The pharmaceutical composition of the present invention is administeredin a pharmaceutically effective amount, and the pharmaceuticallyeffective amount refers to an amount sufficient to treat diseases at areasonable benefit/risk ratio applicable to medical treatment, and aneffective dosage level may be determined according to factors includingtypes of diseases of patients, the severity of disease, the activity ofdrugs, sensitivity to drugs, administration time, administration route,excretion rate, treatment period, factors including simultaneously useddrugs, and other factors well known in the medical field. Thecomposition of the present invention may be administered as anindividual therapeutic agent or in combination with other therapeuticagents, may be administered sequentially or simultaneously withtherapeutic agents in the related art, and may be administered in asingle dose or multiple doses. That is, the total effective amount ofthe composition of the present invention may be administered to apatient in a single dose or may be administered by a fractionatedtreatment protocol, in which multiple doses are administered over a longperiod of time. It is important to administer the composition in aminimum amount that can obtain the maximum effect without any sideeffects, in consideration of all the aforementioned factors, and thisamount may be easily determined by the person skilled in the art.

A dosage of the pharmaceutical composition of the present inventionvaries according to the body weight, age, gender, and health status of apatient, diet, administration time, administration method, excretionrate, and the severity of a disease. A daily dosage thereof may beadministered parenterally in an amount of preferably 0.01 to 200 mg, andmore preferably 0.1 mg to 120 mg per 1 kg of body weight a day based ona Perilla frutescens fermented extract, and a daily dosage thereof maybe administered orally in a single dose or multiple doses in an amountof preferably 0.01 to 200 mg, and more preferably 0.01 to 20 mg per 1 kgof body weight a day based on the Perilla frutescens fermented extractof the present invention. However, since the effective amount may beincreased or decreased depending on the administration route, theseverity of obesity, gender, body weight, age, and the like, the dosageis not intended to limit the scope of the present invention in any way.

The composition of the present invention may be used either alone or incombination with surgery, radiation therapy, hormone therapy,chemotherapy, and methods using a biological response modifier.

The pharmaceutical composition of the present invention may also beprovided in the form of an external preparation including the Perillafrutescens fermented extract as an active ingredient. When thepharmaceutical composition for sleep improvement or for treatment of asleep disorder according to the present invention is used as apreparation for external application to the skin, the pharmaceuticalcomposition may additionally contain auxiliary agents typically used inthe dermatology field, such as any other ingredients typically used inthe preparation for external application to the skin, such as a fattymaterial, an organic solvent, a solubilizing agent, a thickener and agelling agent, a softener, an antidiabetic agent, a suspending agent, astabilizer, a foaming agent, a fragrance, a surfactant, water, an ionicemulsifier, a non-ionic emulsifier, a filler, a metal ion blockingagent, a chelating agent, a preservative, a vitamin, a blocking agent, awetting agent, an essential oil, a dye, a pigment, a hydrophilic activeagent, a lipophilic active agent, or a lipid vesicle. In addition, theingredients may be introduced in an amount generally used in thedermatology field.

When the pharmaceutical composition for sleep improvement or fortreatment of a sleep disorder according to the present invention isprovided as a preparation for external application to the skin, thepharmaceutical composition may be in the form of a formulation such asan ointment, a patch, a gel, a cream, and an aerosol, but is not limitedthereto.

In addition, the present invention provides a health functional foodcomposition comprising a Perilla frutescens fermented extract forprevention or alleviation of a sleep disorder.

Since the Perilla frutescens fermented extract is the same as that usedfor the pharmaceutical composition, the description thereof will bereplaced with the above description thereof.

The type of health functional food is not particularly limited. Examplesthereof include drinks, meats, sausages, bread, biscuits, rice cake,chocolate, candies, snacks, confectioneries, pizza, instant noodles,other noodles, gum, dairy products including ice cream, various soups,drinking water, alcoholic beverages and vitamin complexes, milk productsand dairy products, and the like, and include all health functionalfoods in a typical sense.

The Perilla frutescens fermented extract of the present invention may beadded as is to food or may be used together with other foods or foodingredients and may be appropriately used by a typical method. Themixing amount of the active ingredient may be suitably determineddepending on its purpose of use (for prevention or alleviation). Ingeneral, the amount of the compound in the health food may be 0.1 to 90parts by weight of the total food weight. However, in the case oflong-term intake for the purpose of health and hygiene, or for thepurpose of controlling health, the amount may be equal to or less thanthe above range, and the effective ingredient may be used in an amountequal to or more than the above range due to no problem in terms ofsafety.

Other ingredients are not particularly limited, except that the healthfunctional beverage composition of the present invention contains thecompound of the present invention as an essential ingredient at anindicated ratio, and the health functional beverage composition of thepresent invention may contain various flavoring agents like a typicalbeverage, natural carbohydrates, and the like as an additionalingredient. Examples of the above-described natural carbohydratesinclude typical sugars such as monosaccharides, for example, glucose,fructose and the like; disaccharides, for example, maltose, sucrose andthe like; and polysaccharides, for example, dextrin, cyclodextrin andthe like, and sugar alcohols such as xylitol, sorbitol, and erythritol.As the flavoring agent except for those described above, a naturalflavoring agent (thaumatin, a stevia extract (for example, rebaudiosideA, glycyrrhizin and the like), and a synthetic flavoring agent(saccharin, aspartame and the like) may be advantageously used. Theproportion of the natural carbohydrate is generally about 1 to 20 g, andpreferably about 5 to 12 g per 100 g of the composition of the presentinvention.

The Perilla frutescens fermented extract of the present invention maycontain various nutrients, vitamins, minerals (electrolytes), flavoringagents such as synthetic flavoring agents and natural flavoring agents,colorants and fillers (cheese, chocolate, and the like), pectic acid andsalts thereof, alginic acid and salts thereof, organic acids, protectivecolloid thickeners, pH adjusting agents, stabilizers, antiseptics,glycerin, alcohols, carbonating agents used in a carbonated beverage, orthe like, in addition to those described above. In addition, the Perillafrutescens fermented extract of the present invention may contain fruitpulp for the preparation of natural fruit juices and fruit juicebeverages and vegetable beverages. These ingredients may be used eitheralone or in combinations thereof. The proportion of these additives isnot significantly important, but is generally selected within a range of0.1 to 20 parts by weight per 100 parts by weight of the Perillafrutescens fermented extract of the present invention.

In addition, the present invention provides a composition comprising aPerilla frutescens fermented extract for sleep improvement.

Since the Perilla frutescens fermented extract is the same as that usedfor the pharmaceutical composition, the description thereof will bereplaced with the above description thereof.

The composition of the present invention is preferably any one or morecompositions selected from the group consisting of a food composition, acosmetic composition, a dye composition, a pharmaceutical composition,and a quasi-drug composition, but is not limited thereto.

When the composition of the present invention is formulated into acosmetic composition, the content of the Perilla frutescens fermentedextract is 0.0001 to 10 wt%, preferably 0.01 to 5.0 wt%, based on thetotal weight of the cosmetic composition. In order to achieve theminimum effect of alleviating or preventing skin cancer, the content ofthe Perilla frutescens fermented extract is preferably no less than theabove minimum value, and the content of the Perilla frutescens fermentedextract is preferably no more than the above maximum value consideringreduced usability and applicability to various formulations according toexcess addition. In this case, it is preferred that the content of thePerilla frutescens fermented extract is appropriately adjusted withinthe above range according to the content of the ingredients contained inthe formulation or cosmetic composition.

The ingredients included in the cosmetic composition of the presentinvention include ingredients typically used for the cosmeticcomposition in addition to the Perilla frutescens fermented extract asan active ingredient, and includes, for example, a typical adjuvant suchas an antioxidant, a stabilizer, a solubilizer, a vitamin, a pigment,and a flavoring agent, and a carrier.

The cosmetic composition of the present invention may be prepared intoany typical formulation prepared in the art, and may be formulated intoa cosmetic such as, for example, softening lotion, astringent lotion,nourishing lotion, nourishing cream, massage cream, essence, eye cream,eye essence, cleansing cream, cleansing foam, cleansing water, packs,gel, powder, body lotion, body cream, body oil, and body essence.

When the formulation of the present invention is a paste, a cream or agel, an animal oil, a vegetable oil, a wax, paraffin, starch,tragacanth, a cellulose derivative, a polyethylene glycol, silicone,bentonite, silica, talc, zinc oxide, or the like may be used as acarrier ingredient.

When the formulation of the present invention is a powder or a spray,lactose, talc, silica, aluminum hydroxide, calcium silicate, or apolyamide powder may be used as the carrier ingredient, and inparticular, when the formulation of the present invention is a spray,the formulation may additionally include a propellant such aschlorofluorohydrocarbon, propane/butane or dimethyl ether.

When the formulation of the present invention is a solution or anemulsion, a solvent, a solubilizer or an emulsifier is used as thecarrier ingredient, and examples thereof include water, ethanol,isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylglycol oil, glycerol aliphaticesters, polyethylene glycol or fatty acid esters of sorbitan.

When the formulation of the present invention is a suspension, a liquiddiluent such as water, ethanol or propylene glycol, a suspension such asethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester andpolyoxyethylene sorbitan ester, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar, tragacanth, or the like may be used asthe carrier ingredient.

When the formulation of the present invention is a surfactant-containingcleanser, an aliphatic alcohol sulfate, an aliphatic alcohol ethersulfate, sulphosuccinic acid monoester, isethionate, an imidazoliniumderivative, methyltaurate, a sarcosinate, fatty acid amide ethersulfate, alkylamido betaine, an aliphatic alcohol, fatty acid glyceride,fatty acid diethanolamide, a vegetable oil, a lanolin derivative, anethoxylated glycerol fatty acid ester, or the like may be used as thecarrier ingredient.

In addition, the present invention provides a sleep aid including aPerilla frutescens fermented extract.

Since the Perilla frutescens fermented extract is the same as that usedfor the pharmaceutical composition, the description thereof will bereplaced with the above description thereof.

The sleep aid, unlike a sleeping drug, refer to a generic drug having asleep-inducing or sedative effect, which may be purchased without aprescription from a professional.

In addition, the present invention provides a fiber comprising a Perillafrutescens fermented extract for sleep improvement.

Since the Perilla frutescens fermented extract is the same as that usedfor the pharmaceutical composition, the description thereof will bereplaced with the above description thereof.

The fiber of the present invention refers to all fibers exhibiting thesleep improvement effect due to the Perilla frutescens fermentedextract, such as a fiber prepared using the Perilla frutescens fermentedextract as a raw material, a fiber dyed using the Perilla frutescensfermented extract as a dye, or a fiber in which the Perilla frutescensfermented extract is attached to the fiber surface by spraying and thelike, and is preferably a fiber dyed using the Perilla frutescensfermented extract as a dye.

The fiber may be used in any of the products capable of affecting thesleeping environment, and is preferably included in any one or moreproducts selected from the group consisting of bedding, clothes,curtains, carpets, indoor shoes, towels, wallpaper, interior fabriccoverings, dolls, and eye patches, but is not limited thereto.

The bedding refers to bedlinen and a sleeping pad (a quilt, a sleepingmat), pillows, cushions, and the like required to sleep, the clothesrefer to pajamas, underwear or socks worn during sleeping, and theinterior fabric coverings refer to fabric coverings used to cover andstore furniture, such as chairs or desks, decorations, and appliances,due to contamination or other reasons, but these products are notlimited thereto.

In addition, the present invention provides a fragrance compositioncomprising a Perilla frutescens fermented extract.

Since the Perilla frutescens fermented extract is the same as that usedfor the pharmaceutical composition, the description thereof will bereplaced with the above description thereof.

The fragrance refers to all materials used to produce a scent, such asan aroma.

The fragrance composition may be included without limitation as long asthe fragrance composition is a product used for a use of producing ascent while being capable of exhibiting the sleep improvement effect dueto the Perilla frutescens fermented extract, but is preferably includedin any one or more products selected from the group consisting ofperfumes, fragrant herbs, oils, fragrances, detergents, and preparationsfor external application to the skin. The preparation for externalapplication to the skin includes, all products necessary for bathing,such as soap, a face wash or a bathing agent, but is not limitedthereto.

The amount of the Perilla frutescens fermented extract included in theproducts may be appropriately adjusted and included in order to achievea desired effect according to a conventional technique in the art.

In addition, the present invention provides a method for treatment of asleep disorder, the method comprising a step of administering a Perillafrutescens fermented extract to a patient with a sleep disorder.

Since the Perilla frutescens fermented extract and the sleep disorderare the same as the Perilla frutescens fermented extract and the sleepdisorder of the pharmaceutical composition, the description thereof willbe replaced with the above description thereof.

In addition, the present invention provides a use of a Perillafrutescens fermented extract for use in the preparation of a compositionfor treatment of a sleep disorder.

Since the Perilla frutescens fermented extract and the sleep disorderare the same as the Perilla frutescens fermented extract and the sleepdisorder of the pharmaceutical composition, the description thereof willbe replaced with the above description thereof.

In addition, the present invention provides a Perilla frutescensfermented extract for use in the prevention or treatment of a sleepdisorder.

Since the Perilla frutescens fermented extract and the sleep disorderare the same as the Perilla frutescens fermented extract and the sleepdisorder of the pharmaceutical composition, the description thereof willbe replaced with the above description thereof.

Advantageous Effects

Therefore, in the present invention, the Perilla frutescens fermentedextract, compared with an unfermented Perilla frutescens extract,significantly shortens sleep latency and significantly increases totalsleeping time, and thus the Perilla frutescens fermented extract iseffective as a composition for prevention, alleviation, or treatment ofa sleep disorder or for sleep improvement, and can be also effectivelyused in a treatment method for a sleep disorder.

DESCRIPTION OF DRAWINGS

FIG. 1 illustrates the measurement results of sleep latency afterinducing sleep by administering pentobarbital to rats to which a Perillafrutescens extract ( Perilla-W) or a Perilla frutescens fermentedextract ( Perilla-B) was administered. Physiological saline wasadministered to a control, and diazepam was administered to Dia(positive control). It could be confirmed that when the Perillafrutescens extract was administered, sleep latency was the shortest,which was a value significantly decreased compared to the Perillafrutescens extract or the positive control group.

FIG. 2 illustrates the measurement results of total sleeping time afterinducing sleep by administering pentobarbital to rats to which a Perillafrutescens extract ( Perilla-W) or a Perilla frutescens fermentedextract ( Perilla-B) was administered. Physiological saline wasadministered to a control, and diazepam was administered to Dia(positive control). It could be confirmed that when the Perillafrutescens fermented extract was administered, total sleeping time wassignificantly increased compared to the Perilla frutescens extract.

FIG. 3 illustrates the measurement results of sleep latency afterinducing sleep by administering pentobarbital to rats to which a Perillafrutescens extract ( Perilla-W) or a Perilla frutescens fermentedextract ( Perilla-B, Perilla-L, and Perilla-S) was administered.Physiological saline was administered to a control. It could beconfirmed that when the Perilla frutescens extracts were eachadministered, sleep latency was significantly decreased compared to thePerilla frutescens extract.

FIG. 4 illustrates the measurement results of total sleeping time afterinducing sleep by administering pentobarbital to rats to which a Perillafrutescens extract ( Perilla-W) or a Perilla frutescens fermentedextract ( Perilla-B, Perilla-L, and Perilla-S) was administered.Physiological saline was administered to a control. It could beconfirmed that when the Perilla frutescens extracts were eachadministered, total sleeping time was significantly increased comparedto the Perilla frutescens extract.

MODES OF THE INVENTION

Hereinafter, the present invention will be described in more detailthrough Examples. These Examples are only for exemplifying the presentinvention, and it should be obvious to a person with ordinary skill inthe art that the scope of the present invention is not to be interpretedas being limited by these Examples.

Example 1 Preparation of Perilla Frutescens Extract and FermentedProduct Thereof

Perilla frutescens leaves were subjected to hot water extraction at 80°C. and sterilized at 121° C. for 20 minutes ( Perilla-W). A Perillafrutescens fermented extract was prepared by fermenting the sterilizedPerilla frutescens hot water extract with a bacillus, lactobacillus, oryeast.

Specifically, after bacillus subtilis as one species of bacillus,lactobacillus rhamnosus as one species of lactobacillus, orSaccharomyces cerevisiae as the yeast was each inoculated into thePerilla frutescens extract, fermented extracts of a Perilla frutescensbacillus subtilis fermented product ( Perilla-B), a Perilla frutescenslactobacillus rhamnosus fermented product ( Perilla-L), and aSaccharomyces cerevisiae fermented product ( Perilla-S) were prepared byfermenting the one species for 5 days while being subjected to shakingculture at 140 rpm in an environment of a temperature of 25° C. and ahumidity of 80%.

Example 2 Sleep Improvement Effects of Perilla Frutescens FermentedExtract 2-Comparison of Sleep Improvement Effects with ExistingSedatives

The sleep improvement effects of the Perilla frutescens fermentedextract and conventionally sold sedatives were intended to be confirmedfrom comparison of sleep latency and total sleeping time.

Specifically, 0.9% physiological saline, 10 mg/kg of the Perillafrutescens extract ( Perilla-W) or fermented extract thereof (Perilla-B) prepared in [Example 1], and 1 mg/kg of diazepam (Myung InPharm. Co., Ltd.) were each orally administered to ICR mice (OrientBio).30 minutes after the administration of the test materials, 45 mg/kg of anerve stabilizer pentobarbital (HANLIM PHARM. Co., Ltd.) wasintraperitoneally administered to induce sleep. After the administrationof pentobarbital, the time required to go into deep sleep (sleeplatency) and the total sleep maintenance time (total sleeping time) weremeasured for each test material administration group. Physiologicalsaline and diazepam were used as a control and a positive control,respectively.

As a result, as illustrated in [FIG. 1 ], it was confirmed that when thePerilla-W was administered, the sleep latency (261 seconds) of thePerilla-W-administered group was reduced by about 20% compared to thesleep latency (325 seconds) of the control, and the sleep latency (180seconds) of the Perilla-B-administered group was reduced by about 45%compared to the sleep latency of the control, and thus was moresignificantly reduced compared to the Perilla-W-administered group. Inparticular, a significant effect was confirmed by confirming that thePerilla frutescens fermented extract exhibited a sleep latency reducedby 10% or more compared to when the positive control diazepam was used(220 seconds).

In addition, as illustrated in [FIG. 2 ], it was confirmed that comparedto the total sleeping time (46 minutes) of the control, the totalsleeping time was increased by about 123% (57 minutes) when thePerilla-W was administered, and the total sleeping time was increased byabout 138% (68 minutes) when the Perilla-B was administered, and thuswas more significantly increased compared to that of thePerilla-W-administered group.

2-2 Comparison of Sleep Improvement Effects Per Fermentation Strain

It was intended to confirm whether there is a difference in sleepimprovement effects between fermentation strains fermenting the Perillafrutescens extract. As the fermentation strain, a bacillus,lactobacillus, or yeast was used.

Specifically, sleep latency and total sleeping time were measured in thesame manner as in Example <2-1> using 0.9% physiological saline and 10mg/kg of the Perilla frutescens extract ( Perilla-W) or fermentedextract thereof ( Perilla-B, Perilla-L, and Perilla-S) prepared in[Example 1].

As a result, as illustrated in [FIG. 3 ], compared to the sleep latency(350 seconds) of the control, the sleep latency of thePerilla-W-administered group was reduced by about 25% (261 seconds). Itwas shown that the sleep latency was reduced by about 49% (180 seconds),about 44% (198 seconds), and about 42% (206 seconds) in the case ofadministration of Perilla frutescens fermented extracts Perilla-B,Perilla-L, and Perilla-S, respectively. That is, it could be confirmedthat when the Perilla frutescens fermented extracts were administered,sleep latency was significantly shortened compared to when the Perillafrutescens extract was administered, and among them, the fermentationcase using a bacillus was best in effect.

In addition, as illustrated in [FIG. 4 ], it was shown that when thePerilla-W was administered, the total sleeping time was increased byabout 123% (57 minutes) compared to the total sleeping time (46 minutes)of the control, and it was shown that in the case of administration ofPerilla frutescens fermented extracts Perilla-B, Perilla-L, andPerilla-S, the total sleeping time was increased by about 148% (68minutes), about 139% (64 minutes), and about 141% (65 minutes),respectively compared to the total sleeping time of the control. Thatis, it could be confirmed that when the Perilla frutescens fermentedextracts were administered, total sleeping time was significantlyincreased compared to when the Perilla furtescens extract wasadministered, and among them, the fermentation case using a bacillus wasbest in effect.

Preparation Example

1. Preparation of health functional beverage Vitamins 0.5 wt% Dietaryfiber 4.0 wt% Liquid fructose 93.0 wt% Emulsifier 1.0 wt% Flavor 0.5 wt%Perilla frutescens fermented extract 1.0 wt%

The composition was mixed with purified water such that the total volumebecame 50 ml. A final mixed solution obtained by allowing the mixedsolution to pass through a 2 to 3 µm filter to remove suspended matterwas sterilized at 90 to 93° C. for 15 to 20 seconds and filled in a 50ml bottle and sterilized at 80 to 85° C. for 15 to 20 minutes, therebycompleting a health functional beverage product.

2. Preparation of lotion Hydroxyethylene cellulose (2% aqueous solution)12.0 wt% Xanthan gum (2% aqueous solution) 2.0 wt% 1,3-butylene glycol6.0 wt% Glycerin 4.0 wt% Sodium hyaluronate (1 % aqueous solution) 5.0wt% Ion exchanged water 73.0 wt% Perilla frutescens fermented extract3.0 wt% A lotion was prepared by a typical lotion preparation method.

3. Preparation of fragrance 95% ethanol 65.0 to 75.0 wt% Perillafrutescens fermented extract 25.0 to 35.0 wt%

After the ethanol and the Perilla frutescens fermented extract weremixed, a fragrance was prepared by stirring the resulting mixture atroom temperature for 12 to 20 minutes.

4. Preparation of bathing agent Sodium hydrogen carbonate 70.0 wt%Anhydrous sodium sulfate 29.0 wt% Perilla frutescens fermented extract1.0 wt%

After the sodium bicarbonate and anhydrous sodium sulfate were stirredwith a V-type mixer until the mixture became uniform, the Perillafrutescens fermented extract was added thereto, and the resultingmixture was sufficiently stirred until the mixture again became uniform,thereby preparing a bathing agent.

INDUSTRIAL APPLICABILITY

Therefore, in the present invention, the Perilla frutescens fermentedextract, compared with an unfermented Perilla frutescens extract,significantly shortens sleep latency and significantly increases totalsleeping time, and thus the Perilla frutescens fermented extract iseffective as a composition for prevention, alleviation, or treatment ofa sleep disorder or for sleep improvement, and can be also effectivelyused in a treatment method for a sleep disorder, so that the presentinvention is highly industrially applicable.

1. A composition comprising a Perilia frutescens fermented extract,wherein the Perilla frutescens fermented extract is obtained bysubjecting an extract of Perilla frutescens with water, a C₁ to C₄organic solvent, or a mixture thereof as a solvent, to a fermentationemploying a fermentation microorganism comprising any one or morestrains selected from the group consisting of bacillus subtilis,lactobacillus rhamnosus, and Saccharomyces cerevisiae.
 2. Thecomposition of claim 1, wherein the fermented extract is extracted fromany one or more sites selected from the group consisting of leaves,stems, flowers, fruit, and seeds of Perilla frutescens.
 3. Thecomposition of claim 1, wherein the fermentation is performed at 5° C.to 80° C. for 30 minutes to 10 days.
 4. The composition of claim 1,which is a food composition or a dietary supplement, and furthercomprises an additive selected from the group consisting of a vitamin,an electrolyte, a flavoring agent, a colorant, a filler, a pectic acidand a salt thereof, an alginic acid and a salt thereof, an organic acid,a protective colloid thickener, a pH adjusting agent, a stabilizer, anantiseptic, glycerin, an alcohol, a carbonating agent, a dietary fiber,fruit pulp, and a combination thereof.
 5. The composition of claim 4,wherein the food composition is a beverage or a solid food.
 6. Thecomposition of claim 5, wherein the food composition comprises dietaryfiber, vitamins, or a combination thereof, as the additive.
 7. Thecomposition of claim 5, wherein the beverage is a carbonated beverageand comprises a carbonating agent.
 8. The composition of claim 5,wherein the solid food is a sausage, bread, biscuit, rice cake,chocolate, candy, confectionery, pizza, instant noodle, fresh noodle,chewing gum, a dairy product, or a combination thereof.
 9. Thecomposition of claim 4, wherein the composition is in a solidpreparation selected from a tablet, a pill, a powder, a granule, acapsule, or a combination thereof.
 10. The composition of claim 4,wherein the composition is in a liquid preparation selected from asuspension, an emulsion, a syrup, a soup, or a combination thereof. 11.The composition of claim 1, which is a sleep aid formulation.